Publication
Copy number architectures define treatment-mediated selection of lethal prostate cancer clones
Publisher:
Springer Science and Business Media LLC
Date:
10-08-2023
DOI:
10.1038/S41467-023-40315-9
Abstract: Despite initial responses to hormone treatment, metastatic prostate cancer invariably evolves to a lethal state. To characterize the intra-patient evolutionary relationships of metastases that evade treatment, we perform genome-wide copy number profiling and bespoke approaches targeting the androgen receptor (AR) on 167 metastatic regions from 11 organs harvested post-mortem from 10 men who died from prostate cancer. We identify erse and patient-unique alterations clustering around the AR in metastases from every patient with evidence of independent acquisition of related genomic changes within an in idual and, in some patients, the co-existence of AR -neutral clones. Using the genomic boundaries of pan-autosome copy number changes, we confirm a common clone of origin across metastases and diagnostic biopsies, and identified in in idual patients, clusters of metastases occupied by dominant clones with erged autosomal copy number alterations. These autosome-defined clusters are characterized by cluster-specific AR gene architectures, and in two index cases are topologically more congruent than by chance ( p -values 3.07 × 10 −8 and 6.4 × 10 −4 ). Integration with anatomical sites suggests patterns of spread and points of genomic ergence. Here, we show that copy number boundaries identify treatment-selected clones with putatively distinct lethal trajectories.